Nature of intercalator amiloride-nucelobase stacking. An empirical potential and ab initio electron correlation study

A rigid-body systematic search technique was applied to stacked complexes of the novel AT-specific intercalator, amiloride, with each of the four DNA bases (A, T, C, G) and two Watson-Crick base pairs (AT and GC). Gas-phase calculations were carried out using the Cornell empirical molecular potential with a set of ab initio-optimized atomic charges. At selected points on the ligand-nucleobase potential energy surface, empirical intermolecular interaction energy values were found to be in good agreement with the ab initio MP2/6-31++G(d,p) energies corrected for basis set superposition errors. This result supports the application of the systematic search technique to larger model systems. The general features of the amiloride-base and amiloride-base pair intermolecular potential energy surfaces were found to be different in the case of adenine and thymine compared to guanine and cytosine, resulting in more orientational and translational freedom for amiloride in the former case. In addition, the interaction of amiloride with adenine and thymine nucleobases is significantly more dispersion-controlled than that with guanine and cytosine, where the electrostatic energy contributes up to a third of the total intermolecular energy. Amiloride in the base pair complexes is overlapped with guanine and adenine. Thymine and cytosine are exposed, and the interaction of the ligand with the pyrimidine nucleobases appears to be exclusively due to electrostatic forces.